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Regulation of WNK signaling by potassium and Mo25: structure, function and physiology

Award Number: R01DK110358
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Mutations in human WNK (With No Lysine) kinases are associated with hyperkalemia, hypertension and chronic kidney disease. However, despite extensive characterization of (patho)physiological roles of WNKs in the kidney and extrarenal tissues, there is surprisingly little understanding of how WNKs themselves are regulated. WNKs regulate epithelial ion transport in the mammalian kidney. The applicants’ long-term goal is to achieve mechanistic understanding of epithelial ion transport mechanisms relevant to human kidney function. Chloride ion is known to regulate WNKs. The overall objective of this application is to define and understand new mechanisms of WNK regulation. This renewal application builds on three significant advances from the currently funded grant. First, potassium inhibits Drosophila and mammalian WNKs through chloride-independent mechanisms. Second, the scaffold protein Mo25 (Mouse protein 25/Cab39) is an important regulator of WNK signaling, and activates WNKs independent of its known effects on SPAK (Ste20-related proline alanine rich kinase) and OSR1 (oxidative stress response) kinases. Third, potassium and Mo25 have differential effects on the kidney-expressed mammalian WNKs 1, 3 and 4. The central hypothesis is that potassium and Mo25 directly regulate WNK kinase activity, with differential effects on mammalian WNK isoforms. Guided by strong preliminary data, the central hypothesis will be tested by pursuing three specific aims: 1) Determine the mechanism and physiological consequences of WNK regulation by potassium; 2) Elucidate novel mechanisms of Mo25 regulation of WNK signaling; and 3) Determine the molecular basis for differential WNK isoform regulation by potassium and Mo25. The approach is innovative by leveraging insights from biophysical and structural studies to determine molecular mechanisms of epithelial ion transport regulation, using a unique platform, the Drosophila Malpighian tubule, that has powerful molecular genetic tools and tractable physiologic readouts. Assays have been established, and demonstrated feasible in the investigators’ hands, to: 1) identify WNK potassium binding sites, generate potassium-insensitive WNK mutants, and test their effects on transepithelial ion transport; 2) determine how Mo25 regulates WNK activity in vitro and in the tubule, and probe the interactions between Mo25, potassium and chloride in WNK regulation; and 3) test differences in potassium and Mo25 regulation of WNKs 1, 3 and 4. Successful completion of the proposed studies will elucidate the most comprehensive mechanistic understanding of WNK regulation achieved to date. This is significant, because delineation of the importance of these WNK regulatory mechanisms in various (patho)physiological contexts, together with the molecular insights gained from the studies proposed here, will allow the development of targeted approaches to therapeutically modulate WNK signaling. This has translational impact in a broad range of conditions, including the treatment of dyskalemias, salt-sensitive hypertension, cardio- and cerebrovascular disease, and kidney disease.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $447,906 )
2024	2024	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	7/16/2024	NON-COMPETING CONTINUATION	$447,906
														Subtotal = $447,906

Issue Date FY: 2023 ( Subtotal = $466,570 )
2023	2023	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	9	6/22/2023	NON-COMPETING CONTINUATION	$466,570
2023	2020	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	11/21/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $466,570

Issue Date FY: 2022 ( Subtotal = $466,570 )
2022	2022	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	8	8/5/2022	NON-COMPETING CONTINUATION	$466,570
2022	2021	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	7	10/27/2021	COMPETING CONTINUATION	$20,752
2022	2020	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	10/27/2021	NON-COMPETING CONTINUATION	-$20,752
														Subtotal = $466,570

Issue Date FY: 2021 ( Subtotal = $474,831 )
2021	2021	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	8/24/2021	COMPETING CONTINUATION	$474,831
														Subtotal = $474,831

Issue Date FY: 2020 ( Subtotal = $343,125 )
2020	2020	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	5/15/2020	NON-COMPETING CONTINUATION	$343,125
														Subtotal = $343,125

Issue Date FY: 2019 ( Subtotal = $343,125 )
2019	2019	UNIVERSITY OF UTAH, THE	201 S PRESIDENT CIRCLE RM 408	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	6/5/2019	NON-COMPETING CONTINUATION	$343,125
2019	2018	UNIVERSITY OF UTAH, THE	201 S PRESIDENT CIRCLE RM 408	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/11/2019	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $343,125

Issue Date FY: 2018 ( Subtotal = $418,687 )
2018	2018	UNIVERSITY OF UTAH, THE	201 S PRESIDENT CIRCLE RM 408	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	8/17/2018	SUPPLEMENT FOR EXPANSION	$75,750
2018	2018	UNIVERSITY OF UTAH, THE	201 S PRESIDENT CIRCLE RM 408	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	6/5/2018	NON-COMPETING CONTINUATION	$342,937
														Subtotal = $418,687

Issue Date FY: 2017 ( Subtotal = $316,032 )
2017	2017	UNIVERSITY OF UTAH, THE	201 S PRESIDENT CIRCLE RM 408	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	3	7/20/2017	NON-COMPETING CONTINUATION	$340,782
2017	2016	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	5/4/2017	NEW	-$364,500
2017	2016	UNIVERSITY OF UTAH, THE	201 S PRESIDENT CIRCLE RM 408	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	5/8/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$339,750
														Subtotal = $316,032

Issue Date FY: 2016 ( Subtotal = $364,500 )
2016	2016	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/13/2016	NEW	$364,500
														Subtotal = $364,500

Grand Total All Awards = $3,641,346

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Regulation of WNK signaling by potassium and Mo25: structure, function and physiology

Award Number: R01DK110358

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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